DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I and species of SEQ ID NO:10 in the reply filed on 8/20/25 is acknowledged.
Claim Status
The amendments filed 8/20/25 are acknowledged. Claims 13, 25, 27, 32-34, 36-39, 41-43, 45-46, 61 and 67-85 are cancelled.
Claims 1-12, 14-24, 26, 28-31, 35, 40, 44, 47-60, and 62-66 are pending. Claims 13, 20-36, and 38-85 are cancelled. Claims 2-3, 11, 14-15, and 17-18 are amended. Claims 19-24, 26, 28-31, 35, 40, 44, 47-60, and 62-66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/20/25.
Claims 2-11 and 14-18 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement filed on 8/20/25 has been considered. A signed copy is enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Hyperlinks
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraph [0387]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Trademarks
The use of numerous trademarks has been noted in this application on multiple pages including paragraph [0150], [0161], [0165]-[0166], [0168], [0172], [0176], [0178]-[0179], and [0182]. They should be capitalized wherever they appear and be accompanied by the generic terminology.
Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as trademarks. It is noted that the cited occurrences of improper use are only exemplary and applicant should review the specification to correct any other use of trademarks.
Claim Objections
Claim 2 is objected to because of the following informalities: the claims recites “wherein the composition comprising” and “polysorbate 20, and comprising” which should read “wherein the composition comprises” and “polysorbate 20, and comprises”. Appropriate correction is required.
Claim 18 is objected to because of the following informalities: the claims recites “comprising the chemotherapeutic agent doxorubicin” which should read “wherein the composition further comprises . Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-11 and 14-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a composition (also see rejection under 35 USC 112(b)), which comprises a polypeptide comprising SEQ ID NO:10, along with an excipient, buffer, and a surfactant, wherein the excipient is 8.8% weight/volume sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% polysorbate 20, comprising pH of 6.7. The composition can optionally comprise other agents and therapeutics. The composition must have the specific function of retaining at least 90% stability for a time period greater than 6 months when kept at 2-8C or 5C relative to an identical protein kept under otherwise identical conditions for greater than 6 months at -20C or -70C. The specification has provided examples regarding STM 434 formulated in a sterile aqueous solution intended for IV administration containing 70 mg/mL STM 43, 10 mM potassium phosphate buffer, 8.8% (w/v) sucrose, 0.006% (w/v) polysorbate 20, wherein the composition had a pH of 6.7 (see paragraph [00322]). However, the STM434 composition was kept at both 2-8C and -20C, so it is unclear if this composition meets the functional requirements of the claims. It is also unclear if SEQ ID NO:10 is the same as STM434. The protein must all be able to meet the functional requirements for stability in any of the extremely broad compositions that encompass millions of possible combinations of the required components. The specification provides no guidance regarding which additional specific composition components must be present to achieve the required functional properties. Further, Applicant has supplied only a single formulation species, which is incompletely described. The single species is not sufficiently representative of the broad genus of claimed formulations. Therefore, the specification provides insufficient written description to support the genus of compositions encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides or compositions, regardless of the complexity or simplicity of the method of isolation or identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The demonstration that a limited number of specific peptide formulations can be produced in this formulation does not correlate to, generally, the ability of all peptides to be included in a formulation that would be made by the described method. As taught by Chang et al, proteins typically have a wide range of stability issues as a result of their complexity and delicate structural stability. See Chang et al, page 1, first paragraph (Chang, B.S. and Hershenson, S. 2002. Practical approaches to protein formulation development in "Rationale Design of stable protein formulations-theory and practice" (J.F. Carpenter and M.C. Manning eds.) Kluwer Academic/Plenum publishers, New York. pp. 1-25.) Chang et al also describe various conditions that accelerate protein degradation, which affect specific peptides differently depending on the physical and biological properties of the peptides. See Chang et al, page 5, tables 3 and 4. Chang also states that because proteins are complex molecules composed of numerous reactive chemical groups and delicate three-dimensional structures, identifying a set of conditions to keep all components stable is virtually impossible. See Chang, page 1, paragraph 1. For the instant composition to include all possible peptides, analogs and mixtures recited in the claims, the formulation components must overcome the challenges posed by the array of physical and biological properties within a class of peptides. As taught by Lassner et al, a basic principle of pharmaceutical protein formulations is that certain instabilities must be overcome. See Lassner et al, US2009/0226530, paragraph [0002]. The specification does not provide substantive evidence that the claimed formulation would provide stability for all of the encompassed polypeptide species, with consideration given to amino acid sequence, protein folding, domain localization and enzymatic or other activity. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the extremely broad genus of claimed formulations, i.e. would not be able to accurately predict which of the species of claimed compositions would result in stable peptide formulations for each claimed protein species, which may have widely divergent physical and biological properties depending on the composition and/or amino acid sequence of the peptide(s). As recently confirmed by the Patent Trial and Appeal Board (PTAB), generating stable pharmaceutical compositions is highly unpredictable. See Denying Institution of Inter Partes Review, decision of the Patent Trial and Appeal Board, Patent No. 8,349,321 B2, paper No. 7, 17 pages; Denying Institution of Inter Partes Review, decision of the Patent Trial and Appeal Board, Patent No. 9,114,166 B2, paper No. 10, 15 pages.
For example, in the decision for the '166 patent, the PTAB noted that "'[t]he exquisite sensitivity of protein structure, function, and stability of the primary sequence does not readily lend itself to a generic approach for protein formulation.' Ex. 1025, 185...' even for closely related proteins, the relative stability and major pathways for degradation might be quite different.'" (see page 12.) These decisions support the concept that generating stable pharmaceutical protein formulation is highly unpredictable.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-11 and 14-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
In claims 2, 4, 16 and 17 recite a concentration of a component, then name a species of component. For example, claim 2 recites “the excipient is 8.8% weight/volume (w/v) sucrose”. It is unclear if the percentage value is the amount of that species in the component genus, or the amount in the whole composition. For example, does the excipient comprise 8.8% sucrose, mixed with other excipients, or is the 8.8% referring to the composition comprising 8.8% sucrose? This analysis is also relevant for the buffer, in addition to the excipient. Claims 4-5, 7-12, and 14-15 depend from claim 2 and are also rejected.
In claims 2, 7, and 9, the phrase “(0 months)” renders the claim indefinite. It is unclear if the term in the parentheses is intended as a limitation of the claim, or is merely exemplary. Further, it is not clear what is encompassed by the term “0 months”. A term could be, for example, 1 day, which is not yet 1 month, but which is the “beginning of the time period”. It is unclear if this time period would be encompassed by “0 months”.
The scope of claims 3-10 are indefinite due to the recitation of both broad and narrow ranges or limitations within the same claim. The claims require broader limitations, including a range of values, combined with several “optional” species that are presented as alternative narrower ranges compared to the range in which they also fall. In each case, the claim has recited a broad limitation followed by a narrower limitation. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 3-6 and 9-10 recite the term “optionally”. The recitation of the optional limitations renders the claims indefinite. The optional phrases introduce ambiguity as to which alternatives are covered by the claim, because the optional limitations are narrower ranges within the broader range recited in the same claim. It is unclear whether the “optional” limitations are required or merely exemplary of possible values within the range. Applicant is reminded that the term “at least” indicates a range. For example, a concentration of “at least 9.0%” is interpreted to mean that the claim encompassed all values between 9.0% and 100%.
Claims 3-5, 7-10, and 15 recite the term “at least” followed by a range. Where the term “at least” is recited with a range, the claim scope is indefinite because the term “at least” references a minimum, and it is impossible for a minimum to be a range.
Claims 3-10 and 15-16 add limitations that broaden the scope of the base claim. Therefore the claims are directed to both a specific composition, with named components and concentrations, but also broader compositions with varying concentrations and components, including additional protein sequences. According to MPEP 608.01(n), the test as to whether a claim is a proper dependent claim is that it shall include every limitation of the claim from which it depends and specify a further limitation of the subject matter claimed. Here, the claims do not further limit the subject matter claimed, and in fact, broaden the subject matter claimed. Therefore, the claims are not proper dependent claims.
The scope of the rejected claims is therefore indefinite. For example:
Claim 3 recites ranges for pH, when base claim 2, from which claim 3 depends, requires a pH of 6.7. Therefore, the dependent claim improperly broadens the pH. The scope is therefore indefinite.
Claim 4 recites sucrose as only an “option” for the excipient, rather than requiring sucrose, and also recites various ranges and values for the concentration of sucrose, when base claim 2, from which claim 4 depends, recites a requirement for 8.8% w/v sucrose. Therefore, the dependent claim improperly broadens both the type of excipient and the concentration of excipient. The scope is therefore indefinite.
Claim 5 requires that the buffer is optionally a potassium phosphate buffer, with optional concentration ranges and values, however, base claim 2, from which claim 5 depends, requires a potassium phosphate buffer with a concentration of 10 mM. Therefore, the dependent claim improperly broadens both the type of buffer and the concentration of buffer. The scope is therefore indefinite.
Claim 6 requires that the buffer is only optionally polysorbate, and only optionally polysorbate 20, with optional concentration ranges and values; however, base claim 2, from which claim 6 depends, requires polysorbate 20 with a concentration of 0.006% w/v. Therefore, the dependent claim improperly broadens both the type of surfactant and the concentration of surfactant. The scope is therefore indefinite.
Claims 7-8 recite ranges and various values for percent stability that include values below 90%, as well as various time periods that are under 6 months. However, base claim 2, from which claims 7-8 depend, requires at least 90% stability, and at least 6 months for the stability. Therefore claims 7-8 improperly broaden the percent and time required for stability. Therefore the dependent claims improperly broaden the claimed composition.
Claims 9-10 recite ranges and various time periods that are under 6 months. However, base claim 2, from which claims 9-10 depend, requires at least 6 months for the stability. Therefore claims 9-10 improperly broaden the time required for stability. Therefore the dependent claims improperly broaden the claimed composition.
Claim 15 recites various ranges and values for protein concentration range, while base claim 2 requires 70 mg/ml. Therefore the dependent claim improperly broadens the scope of the concentration of protein in the claimed composition.
Claim 16 recites a different protein sequence than the one required by base claims. The base claim requires SEQ ID NO:10 (and specifically uses the transition phrase “consisting of”), while the dependent claim recites SEQ ID NO:6, which is a fragment of SEQ ID NO:10. Therefore the dependent claim improperly broadens the claimed composition.
Claims depending from the rejected claims above do not remedy all of the deficiencies listed above and therefore are also rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-11 and 14-18 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 recites the same formulation as base claim 2, therefore claim 17 fails to further limit the subject matter of the claim upon which it depends.
Claims 3-10 and 15-16 add limitations that broaden the scope of the base claim. Therefore the claims are directed to both a specific composition, with named components and concentrations, but also broader compositions with varying concentrations and components, including additional protein sequences. According to MPEP 608.01(n), the test as to whether a claim is a proper dependent claim is that it shall include every limitation of the claim from which it depends and specify a further limitation of the subject matter claimed. Here, the claims do not further limit the subject matter claimed, and in fact, broaden the subject matter claimed. Therefore, the claims are not proper dependent claims.
For example:
Claim 3 recites ranges for pH, when base claim 2, from which claim 3 depends, requires a pH of 6.7. Therefore, the dependent claim improperly broadens the pH.
Claim 4 recites sucrose as only an “option” for the excipient, rather than requiring sucrose, and also recites various ranges and values for the concentration of sucrose, when base claim 2, from which claim 4 depends, recites a requirement for 8.8% w/v sucrose. Therefore, the dependent claim improperly broadens both the type of excipient and the concentration of excipient.
Claim 5 requires that the buffer is optionally a potassium phosphate buffer, with optional concentration ranges and values, however, base claim 2, from which claim 5 depends, requires a potassium phosphate buffer with a concentration of 10 mM. Therefore, the dependent claim improperly broadens both the type of buffer and the concentration of buffer.
Claim 6 requires that the buffer is only optionally polysorbate, and only optionally polysorbate 20, with optional concentration ranges and values; however, base claim 2, from which claim 6 depends, requires polysorbate 20 with a concentration of 0.006% w/v. Therefore, the dependent claim improperly broadens both the type of surfactant and the concentration of surfactant.
Claims 7-8 recite ranges and various values for percent stability that include values below 90%, as well as various time periods that are under 6 months. However, base claim 2, from which claims 7-8 depend, requires at least 90% stability, and at least 6 months for the stability. Therefore claims 7-8 improperly broaden the percent and time required for stability. Therefore the dependent claims improperly broaden the claimed composition.
Claims 9-10 recite ranges and various time periods that are under 6 months. However, base claim 2, from which claims 9-10 depend, requires at least 6 months for the stability. Therefore claims 9-10 improperly broaden the time required for stability. Therefore the dependent claims improperly broaden the claimed composition.
Claim 15 recites various ranges and values for protein concentration range, while base claim 2 requires 70 mg/ml. Therefore the dependent claim improperly broadens the scope of the concentration of protein in the claimed composition.
Claim 16 recites a different protein sequence than the one required by base claims. The base claim requires SEQ ID NO:10 (and specifically uses the transition phrase “consisting of”), while the dependent claim recites SEQ ID NO:6, which is a fragment of SEQ ID NO:10. Therefore the dependent claim improperly broadens the claimed composition.
Claims depending from the rejected claims above do not remedy all of the deficiencies listed above and therefore are also rejected.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
1. Claims 2-11 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Han et al (WO 2010/062383 A2; priority date 11/26/08; published 6/3/10; filed 11/24/09) in view of Mallubhotla, et al (WO 2011/141926 A2; published 11/17/11; filed 5/4/11).
The instant claims are drawn to a composition comprising a solution of a protein, an excipient, a buffer and a surfactant, wherein the protein consists of the sequence of SEQ ID NO:10 in a solution at a concentration of 70 mg/mL, the excipient is 8.8% weight/volume (w/v) sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% (w/v) sucrose, the pH is 6.7, and the protein retains at least 90% stability for a time period of greater than 6 months in solution when kept at 2-8 degrees C, relative to the protein in the composition at the beginning of the time period (0 months) or relative to an identical protein kept under otherwise identical conditions for greater than 6 months.
The formulation allows the protein to retain at least 80% stability for a time period of greater than 1 month in solution when kept at 2-8C or 5C relative to the protein in the composition at the beginning of the time period or relative to an identical protein kept under otherwise identical conditions for greater than 1 month at -20C or -70C. The composition can have SEQ ID NO:10, and the composition can be variable concentrations and agents, which are named within several concentration ranges or pH ranges in the dependent claims 3-10. One species is a formulation wherein the protein can be 70 mg/ml, the excipient can be 8.8% w/v sucrose, the buffer can be 10 mM potassium phosphate buffer, the surfactant can be 0.006% w/v polysorbate 20, and the pH can be 6.7. The protein stability can be determined by one of several methods as recited in instant claim 11.
Han et al describe stabilized actvin IIB receptor polypeptides capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (see entire document, e.g. abstract). The proteins can have amino acid substitution at position 28 to a “W” residue, and a substitution at position 44 to a “T” residue (see entire document, e.g. page 3). These polypeptides can be SEQ ID NO: 6 or 10, which are identical to instant SEQ ID NO: 6 and 10, respectively (see entire document, e.g. page 4, and 19-21). The protein is an svActRIIB-Fc (E28W, S44T) polypeptide (see e.g. Example 1). The composition can comprise the protein in admixture with a pharmaceutical carrier (see entire document, e.g. pages 7 and 27-33). The composition may contain materials for modifying, maintaining, or preserving the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition (see entire document, e.g. page 27-33). The named agents that may be used in combination are mono- or disaccharides or other carbohydrates (see entire document, e.g. page 27), wherein the excipients can include sucrose (see entire document, e.g. page 28), surfactants such as polysorbate 20 (see entire document, e.g. page 27), buffers including phosphate buffers (see entire document, e.g. page 27), and the primary vehicle carrier can be an aqueous solution (see entire document, e.g. page 28). The proteins can be characterized by size-exclusion HPLC (see e.g. Example 2, page39; see also page 42, top paragraph for “SEC analysis” to determine protein stability). The pharmaceutical composition comprising the polypeptide may contain formulation materials for modifying, maintaining, or preserving pH, stability, and other characteristics (see e.g. page 27, particularly lines 7-10).
Han et al do not describe the specific ranges for the components, or name the specific species of formulation of instant claims 2, 16, or 17.
Mallubhotla et al describe liquid formulations for polypeptides containing an Fc domain of an immunoglobulin which is stabilized to maintain activity for a prolonged period of time (see entire document, e.g. abstract and claim 1). The formulations include the use of TNFR-Fc, which is a receptor peptide conjugated to an Fc domain, similar to the polypeptide of instant SEQ ID NO:10. The pharmaceutical composition can comprise a buffer, non-ionic surfactant, a polyol, and other components. Table 5 of Mallubhotla teaches example formulations with sucrose, polysorbate 20, and potassium phosphate buffer salts. SE-HPLC was used to measure aggregation and fragmentation (see entire document, e.g. page 16). The protein can be present in a concentration of 10 to 100 mg/ml (see entire document, e.g. claim 10). The composition comprises 10 to 50 mM potassium phosphate, 0.75 to 3% sucrose, 0.05 mg/ml to 1.0 mg/ml polysorbate at pH 6.0 to pH 7.0 (see entire document, e.g. claim 11). Mallubhotla also teaches the use of SE-HPLC for determining stability (see e.g. Example 2 on page 11, and Example 5 on page 16)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to apply the formulation of Mallubhotla et al to stabilize the proteins of Han et al. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Han et al specifically discloses pharmaceutical formulation and outlines several components, which are routine excipients in the art for protein formulations. Han et al state that the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage (see entire document, e.g. pages 27-28). Further, the instant specification teaches that “those skilled in the art will know to employ one or more excipients that maintain maximal stability of the active form of a polypeptide given, for example, a particular manufacturing or storage condition or a particular mode of administration” (see e.g. paragraph [0102] of the instant specification). The teachings of Mallubhotla et al also recognize that one of skill in the art could alter the combinations to produce the stability of the formulation, for example on Mallubhotla page 15, which states “It is also to be understood by one of ordinary skill in the art that some of these chemicals are incompatible at certain combinations, and accordingly, are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture.” Mallubhotla et al specifically indicates that the formulation is applicable to formulations that comprise Fc domains (see entire document, e.g. abstract), and that the disclosed formulation can prevent aggregation of the fusion protein during long term storage, prevents unwanted cleavage, and maintains activity over time, even at elevated temperatures (see entire document, e.g. pages 8-9). It would be expected, absent evidence to the contrary, that the formulation of Mallubhotla et al would stabilize the proteins of Han et al since they are directed to formulations comprising an Fc domain, and all of the formulation components of Mallubhotla et al fall within the scope of the disclosure of Han et al. The advantages of increased stability and decreased aggregation provides the motivation to make the aforementioned modification of the formulation of Han et al, based on the teachings of Mallubhotla et al, with a reasonable expectation of success.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of formulation components for the protein formulations of Han et al, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). This is especially true in light of the teachings of the instant specification which states that “those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a formulation of the invention that promotes retention in stability of the polypeptide” (see e.g. paragraph [0114] of published application). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
2. Claims 2-11 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al (US 2010/0168020 A1; published 7/1/10; filed 11/25/09) in view of Mallubhotla, et al (WO 2011/141926 A2; published 11/17/11; filed 5/4/11).
The instant claims are drawn to a composition comprising a solution of a protein, an excipient, a buffer and a surfactant, wherein the protein consists of the sequence of SEQ ID NO:10 in a solution at a concentration of 70 mg/mL, the excipient is 8.8% weight/volume (w/v) sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% (w/v) sucrose, the pH is 6.7, and the protein retains at least 90% stability for a time period of greater than 6 months in solution when kept at 2-8 degrees C, relative to the protein in the composition at the beginning of the time period (0 months) or relative to an identical protein kept under otherwise identical conditions for greater than 6 months.
The formulation allows the protein to retain at least 80% stability for a time period of greater than 1 month in solution when kept at 2-8C or 5C relative to the protein in the composition at the beginning of the time period or relative to an identical protein kept under otherwise identical conditions for greater than 1 month at -20C or -70C. The composition can have SEQ ID NO:10, and the composition can be variable concentrations and agents, which are named within several concentration ranges or pH ranges in the dependent claims 3-10. One species is a formulation wherein the protein can be 70 mg/ml, the excipient can be 8.8% w/v sucrose, the buffer can be 10 mM potassium phosphate buffer, the surfactant can be 0.006% w/v polysorbate 20, and the pH can be 6.7. The protein stability can be determined by one of several methods as recited in instant claim 11.
Sun et al describe stabilized actvin IIB receptor polypeptides capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (see entire document, e.g. abstract). The proteins can have amino acid substitution at position 28 to a “W” residue, and a substitution at position 44 to a “T” residue (see entire document, e.g. claim 1). These polypeptides can be SEQ ID NO: 6 or 10, which are identical to instant SEQ ID NO: 6 and 10, respectively (see entire document, e.g. paragraphs [0062]-[0064] and Examples 1 and 2). The composition can comprise the protein in admixture with a pharmaceutical carrier (see entire document, e.g. paragraph [0023). The composition may contain materials for modifying, maintaining, or preserving the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition (see entire document, e.g. paragraphs [0078]-[0095]). The named agents that may be used in combination are mono- or disaccharides or other carbohydrates (see entire document, e.g. paragraphs [0078]-[0095]), wherein the excipients can include sucrose (see entire document, e.g. paragraphs [0078]-[0095]), surfactants such as polysorbate 20 (see entire document, e.g. paragraphs [0078]-[0095]), buffers including phosphate buffers (see entire document, e.g. paragraphs [0078]-[0095]), and the primary vehicle carrier can be an aqueous solution (see entire document, e.g. paragraphs [0078]-[0095]). Sun describes measurement for characterization of the polypeptides using size exclusion chromatography (see e.g. paragraph [0122], [0143]).
Sun et al do not describe the specific ranges for the components, or name the specific species of formulation of instant claims 2, 16, or 17.
Mallubhotla et al describe liquid formulations for polypeptides containing an Fc domain of an immunoglobulin which is stabilized to maintain activity for a prolonged period of time (see entire document, e.g. abstract and claim 1). The formulations include the use of TNFR-Fc, which is a receptor peptide conjugated to an Fc domain, similar to the polypeptide of instant SEQ ID NO:10. The pharmaceutical composition can comprise a buffer, non-ionic surfactant, a polyol, and other components. Table 5 of Mallubhotla teaches example formulations with sucrose, polysorbate 20, and potassium phosphate buffer salts. SE-HPLC was used to measure aggregation and fragmentation (see entire document, e.g. page 16). The protein can be present in a concentration of 10 to 100 mg/ml (see entire document, e.g. claim 10). The composition comprises 10 to 50 mM potassium phosphate, 0.75 to 3% sucrose, 0.05 mg/ml to 1.0 mg/ml polysorbate at pH 6.0 to pH 7.0 (see entire document, e.g. claim 11). Mallubhotla also teaches the use of SE-HPLC for determining stability (see e.g. Example 2 on page 11, and Example 5 on page 16)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use the formulation of Mallubhotla et al to stabilize the proteins of Sun et al. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Sun et al specifically discloses pharmaceutical formulation and outlines several components, which are routine excipients in the art for protein formulations. Sun et al state that the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage (see entire document, e.g. pages 27-28). Further, the instant specification teaches that “those skilled in the art will know to employ one or more excipients that maintain maximal stability of the active form of a polypeptide given, for example, a particular manufacturing or storage condition or a particular mode of administration” (see e.g. paragraph [0102] of published application). The teachings of Mallubhotla et al also recognize that one of skill in the art could alter the combinations to produce the stability of the formulation, for example on page 15, which states “It is also to be understood by one of ordinary skill in the art that some of these chemicals are incompatible at certain combinations, and accordingly, are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture.” Mallubhotla et al specifically indicates that the formulation is applicable to formulations that comprise Fc domains (see entire document, e.g. abstract), and that the disclosed formulation can prevent aggregation of the fusion protein during long term storage, prevents unwanted cleavage, and maintains activity over time, even at elevated temperatures (see entire document, e.g. pages 8-9). It would be expected, absent evidence to the contrary, that the formulation of Mallubhotla et al would stabilize the proteins of Sun et al since they can comprise an Fc domain, and all of the formulations of Mallubhotla et al fall within the scope of the disclosure of Sun et al. The advantages of increased stability and decreased aggregation provides the motivation to make the aforementioned modification of the formulation of Sun et al, based on the teachings of Mallubhotla et al, with a reasonable expectation of success.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of formulation components for the protein formulations of Sun et al, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). This is especially true in light of the teachings of the instant specification which states that “those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a formulation of the invention that promotes retention in stability of the polypeptide” (see e.g. paragraph [0114] of published application). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
1. Claims 2-11 and 14-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 8,410,043 in view of Mallubhotla, et al (WO 2011/141926 A2; published 11/17/11; filed 5/4/11).
The instant claims are drawn to a composition comprising a solution of a protein, an excipient, a buffer and a surfactant, wherein the protein consists of the sequence of SEQ ID NO:10 in a solution at a concentration of 70 mg/mL, the excipient is 8.8% weight/volume (w/v) sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% (w/v) sucrose, the pH is 6.7, and the protein retains at least 90% stability for a time period of greater than 6 months in solution when kept at 2-8 degrees C, relative to the protein in the composition at the beginning of the time period (0 months) or relative to an identical protein kept under otherwise identical conditions for greater than 6 months.
The formulation allows the protein to retain at least 80% stability for a time period of greater than 1 month in solution when kept at 2-8C or 5C relative to the protein in the composition at the beginning of the time period or relative to an identical protein kept under otherwise identical conditions for greater than 1 month at -20C or -70C. The composition can have SEQ ID NO:10, and the composition can be variable concentrations and agents, which are named within several concentration ranges or pH ranges in the dependent claims 3-10. One species is a formulation wherein the protein can be 70 mg/ml, the excipient can be 8.8% w/v sucrose, the buffer can be 10 mM potassium phosphate buffer, the surfactant can be 0.006% w/v polysorbate 20, and the pH can be 6.7. The protein stability can be determined by one of several methods as recited in instant claim 11.
The ‘043 patent describes stabilized actvin IIB receptor polypeptides capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (see entire document, e.g. abstract and claims 1-8). The proteins can have amino acid substitution at position 28 to a “W” residue, and a substitution at position 44 to a “T” residue (see entire document, e.g. claims 1-8). These polypeptides can be SEQ ID NO: 6 or 10, which are identical to instant SEQ ID NO: 6 and 10, respectively (see entire document, e.g. claims 1-8, columns 13-14, and Examples 1 and 2). The composition can comprise the protein in admixture with a pharmaceutical carrier (see entire document, e.g. claim 8).
The ‘043 patent claims do not describe the specific composition or ranges for the components, or name the specific species of formulation of instant claims 2, 16, or 17.
Mallubhotla et al describe liquid formulations for polypeptides containing an Fc domain of an immunoglobulin which is stabilized to maintain activity for a prolonged period of time (see entire document, e.g. abstract and claim 1). The formulations include the use of TNFR-Fc, which is a receptor peptide conjugated to an Fc domain, similar to the polypeptide of instant SEQ ID NO:10. The pharmaceutical composition can comprise a buffer, non-ionic surfactant, a polyol, and other components. Table 5 of Mallubhotla teaches example formulations with sucrose, polysorbate 20, and potassium phosphate buffer salts. SE-HPLC was used to measure aggregation and fragmentation (see entire document, e.g. page 16). The protein can be present in a concentration of 10 to 100 mg/ml (see entire document, e.g. claim 10). The composition comprises 10 to 50 mM potassium phosphate, 0.75 to 3% sucrose, 0.05 mg/ml to 1.0 mg/ml polysorbate at pH 6.0 to pH 7.0 (see entire document, e.g. claim 11). Mallubhotla also teaches the use of SE-HPLC for determining stability (see e.g. Example 2 on page 11, and Example 5 on page 16)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use the formulation of Mallubhotla et al to stabilize the proteins of the ‘043 patent. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The ‘043 patent state that the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage (see entire document, e.g. columns 19-23). Further, the instant specification teaches that “those skilled in the art will know to employ one or more excipients that maintain maximal stability of the active form of a polypeptide given, for example, a particular manufacturing or storage condition or a particular mode of administration” (see e.g. paragraph [0102] of published application). The teachings of Mallubhotla et al also recognize that one of skill in the art could alter the combinations to produce the stability of the formulation, for example on page 15, which states “It is also to be understood by one of ordinary skill in the art that some of these chemicals are incompatible at certain combinations, and accordingly, are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture.” Mallubhotla et al specifically indicates that the formulation is applicable to formulations that comprise Fc domains (see entire document, e.g. abstract), and that the disclosed formulation can prevent aggregation of the fusion protein during long term storage, prevents unwanted cleavage, and maintains activity over time, even at elevated temperatures (see entire document, e.g. pages 8-9). It would be expected, absent evidence to the contrary, that the formulation of Mallubhotla et al would stabilize the proteins of the ‘043 patent since they can comprise an Fc domain, and all of the formulations of Mallubhotla et al fall within the scope of the disclosure of the ‘043 patent. The advantages of increased stability and decreased aggregation provides the motivation to make the aforementioned modification of the formulation of the ‘043 patent, based on the teachings of Mallubhotla et al, with a reasonable expectation of success.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of formulation components for the protein formulations of the ‘043 patent, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). This is especially true in light of the teachings of the instant specification which states that “those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a formulation of the invention that promotes retention in stability of the polypeptide” (see e.g. paragraph [0114] of published application). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent which provides support for the patent claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because only "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined."
2. Claims 2-11 and 14-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 9,273,114 in view of Mallubhotla, et al (WO 2011/141926 A2; published 11/17/11; filed 5/4/11).
The instant claims are drawn to a composition comprising a solution of a protein, an excipient, a buffer and a surfactant, wherein the protein consists of the sequence of SEQ ID NO:10 in a solution at a concentration of 70 mg/mL, the excipient is 8.8% weight/volume (w/v) sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% (w/v) sucrose, the pH is 6.7, and the protein retains at least 90% stability for a time period of greater than 6 months in solution when kept at 2-8 degrees C, relative to the protein in the composition at the beginning of the time period (0 months) or relative to an identical protein kept under otherwise identical conditions for greater than 6 months.
The formulation allows the protein to retain at least 80% stability for a time period of greater than 1 month in solution when kept at 2-8C or 5C relative to the protein in the composition at the beginning of the time period or relative to an identical protein kept under otherwise identical conditions for greater than 1 month at -20C or -70C. The composition can have SEQ ID NO:10, and the composition can be variable concentrations and agents, which are named within several concentration ranges or pH ranges in the dependent claims 3-10. One species is a formulation wherein the protein can be 70 mg/ml, the excipient can be 8.8% w/v sucrose, the buffer can be 10 mM potassium phosphate buffer, the surfactant can be 0.006% w/v polysorbate 20, and the pH can be 6.7. The protein stability can be determined by one of several methods as recited in instant claim 11.
The ‘114 patent describes stabilized actvin IIB receptor polypeptides capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (see entire document, e.g. abstract and claims 1-31). The proteins can have amino acid substitution at position 28 to a “W” residue, and a substitution at position 44 to a “T” residue (see entire document, e.g. claims 1-7). These polypeptides can be SEQ ID NO: 6 or 10, which are identical to instant SEQ ID NO: 6 and 10, respectively (see entire document, e.g. claims 1-7, columns 13-20, and Examples 1 and 2). The composition can comprise the protein in admixture with a pharmaceutical carrier (see entire document, e.g. claim 7).
The ‘114 patent claims do not describe the specific formulation components, including specific ranges for the components, or name the specific species of formulation of instant claims 2, 16, or 17.
Mallubhotla et al describe liquid formulations for polypeptides containing an Fc domain of an immunoglobulin which is stabilized to maintain activity for a prolonged period of time (see entire document, e.g. abstract and claim 1). The formulations include the use of TNFR-Fc, which is a receptor peptide conjugated to an Fc domain, similar to the polypeptide of instant SEQ ID NO:10. The pharmaceutical composition can comprise a buffer, non-ionic surfactant, a polyol, and other components. Table 5 of Mallubhotla teaches example formulations with sucrose, polysorbate 20, and potassium phosphate buffer salts. SE-HPLC was used to measure aggregation and fragmentation (see entire document, e.g. page 16). The protein can be present in a concentration of 10 to 100 mg/ml (see entire document, e.g. claim 10). The composition comprises 10 to 50 mM potassium phosphate, 0.75 to 3% sucrose, 0.05 mg/ml to 1.0 mg/ml polysorbate at pH 6.0 to pH 7.0 (see entire document, e.g. claim 11). Mallubhotla also teaches the use of SE-HPLC for determining stability (see e.g. Example 2 on page 11, and Example 5 on page 16)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use the formulation of Mallubhotla et al to stabilize the proteins of the ‘114 patent. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The ‘114 patent state that the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage (see entire document, e.g. columns 22-27). Further, the instant specification teaches that “those skilled in the art will know to employ one or more excipients that maintain maximal stability of the active form of a polypeptide given, for example, a particular manufacturing or storage condition or a particular mode of administration” (see e.g. paragraph [0102] of published application). The teachings of Mallubhotla et al also recognize that one of skill in the art could alter the combinations to produce the stability of the formulation, for example on page 15, which states “It is also to be understood by one of ordinary skill in the art that some of these chemicals are incompatible at certain combinations, and accordingly, are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture.” Mallubhotla et al specifically indicates that the formulation is applicable to formulations that comprise Fc domains (see entire document, e.g. abstract), and that the disclosed formulation can prevent aggregation of the fusion protein during long term storage, prevents unwanted cleavage, and maintains activity over time, even at elevated temperatures (see entire document, e.g. pages 8-9). It would be expected, absent evidence to the contrary, that the formulation of Mallubhotla et al would stabilize the proteins of the ‘114 patent since they can comprise an Fc domain, and all of the formulations of Mallubhotla et al fall within the scope of the disclosure of the ‘114 patent. The advantages of increased stability and decreased aggregation provides the motivation to make the aforementioned modification of the formulation of the ‘114 patent, based on the teachings of Mallubhotla et al, with a reasonable expectation of success.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of formulation components for the protein formulations of the ‘114 patent, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). This is especially true in light of the teachings of the instant specification which states that “those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a formulation of the invention that promotes retention in stability of the polypeptide” (see e.g. paragraph [0114] of published application). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent which provides support for the patent claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because only "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined."
3. Claims 2-11 and 14-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 19-20 of copending Application No. 18/206,963 in view of Mallubhotla, et al (WO 2011/141926 A2; published 11/17/11; filed 5/4/11).
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn to a composition comprising a solution of a protein, an excipient, a buffer and a surfactant, wherein the protein consists of the sequence of SEQ ID NO:10 in a solution at a concentration of 70 mg/mL, the excipient is 8.8% weight/volume (w/v) sucrose, the buffer is 10 mM potassium phosphate buffer, the surfactant is 0.006% (w/v) sucrose, the pH is 6.7, and the protein retains at least 90% stability for a time period of greater than 6 months in solution when kept at 2-8 degrees C, relative to the protein in the composition at the beginning of the time period (0 months) or relative to an identical protein kept under otherwise identical conditions for greater than 6 months.
The formulation allows the protein to retain at least 80% stability for a time period of greater than 1 month in solution when kept at 2-8C or 5C relative to the protein in the composition at the beginning of the time period or relative to an identical protein kept under otherwise identical conditions for greater than 1 month at -20C or -70C. The composition can have SEQ ID NO:10, and the composition can be variable concentrations and agents, which are named within several concentration ranges or pH ranges in the dependent claims 3-10. One species is a formulation wherein the protein can be 70 mg/ml, the excipient can be 8.8% w/v sucrose, the buffer can be 10 mM potassium phosphate buffer, the surfactant can be 0.006% w/v polysorbate 20, and the pH can be 6.7. The protein stability can be determined by one of several methods as recited in instant claim 11.
The copending application describes stabilized actvin IIB receptor polypeptides capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (see entire document, e.g. abstract and claims 1-7). The proteins can have amino acid substitution at position 28 to a “W” residue, and a substitution at position 44 to a “T” residue (see entire document, e.g. claim 1). These polypeptides can be SEQ ID NO: 6 or 10, which are identical to instant SEQ ID NO: 6 and 10, respectively (see entire document, e.g. claims 2 and 7). The composition can comprise the protein in admixture with a pharmaceutical carrier (see entire document, e.g. claim 19).
The copending application claims do not describe the specific formulation components, including specific ranges for the components, or name the specific species of formulation of instant claims 2, 16, or 17.
Mallubhotla et al describe liquid formulations for polypeptides containing an Fc domain of an immunoglobulin which is stabilized to maintain activity for a prolonged period of time (see entire document, e.g. abstract and claim 1). The formulations include the use of TNFR-Fc, which is a receptor peptide conjugated to an Fc domain, similar to the polypeptide of instant SEQ ID NO:10. The pharmaceutical composition can comprise a buffer, non-ionic surfactant, a polyol, and other components. Table 5 of Mallubhotla teaches example formulations with sucrose, polysorbate 20, and potassium phosphate buffer salts. SE-HPLC was used to measure aggregation and fragmentation (see entire document, e.g. page 16). The protein can be present in a concentration of 10 to 100 mg/ml (see entire document, e.g. claim 10). The composition comprises 10 to 50 mM potassium phosphate, 0.75 to 3% sucrose, 0.05 mg/ml to 1.0 mg/ml polysorbate at pH 6.0 to pH 7.0 (see entire document, e.g. claim 11). Mallubhotla also teaches the use of SE-HPLC for determining stability (see e.g. Example 2 on page 11, and Example 5 on page 16)
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use the formulation of Mallubhotla et al to stabilize the proteins of the copending application. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The copending application states that the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage (see entire document, e.g. reference specification, page 29). Further, the instant specification teaches that “those skilled in the art will know to employ one or more excipients that maintain maximal stability of the active form of a polypeptide given, for example, a particular manufacturing or storage condition or a particular mode of administration” (see e.g. paragraph [0102] of published application). The teachings of Mallubhotla et al also recognize that one of skill in the art could alter the combinations to produce the stability of the formulation, for example on page 15, which states “It is also to be understood by one of ordinary skill in the art that some of these chemicals are incompatible at certain combinations, and accordingly, are easily substituted with different chemicals that have similar properties but are compatible in the relevant mixture.” Mallubhotla et al specifically indicates that the formulation is applicable to formulations that comprise Fc domains (see entire document, e.g. abstract), and that the disclosed formulation can prevent aggregation of the fusion protein during long term storage, prevents unwanted cleavage, and maintains activity over time, even at elevated temperatures (see entire document, e.g. pages 8-9). It would be expected, absent evidence to the contrary, that the formulation of Mallubhotla et al would stabilize the proteins of the copending claims since they can comprise an Fc domain, and all of the formulations of Mallubhotla et al fall within the scope of the disclosure of the copending application. The advantages of increased stability and decreased aggregation provides the motivation to make the aforementioned modification of the composition of the copending application, based on the teachings of Mallubhotla et al, with a reasonable expectation of success.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of formulation components for the protein composition of the copending application, since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). This is especially true in light of the teachings of the instant specification which states that “those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a formulation of the invention that promotes retention in stability of the polypeptide” (see e.g. paragraph [0114] of published application). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent which provides support for the patent claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because only "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined."
Conclusion
No claim is allowed.
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